Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with involvement of the immune system. Steroids and ACTH have been used to treat MS but are effective only in a subgroup of patients. I have found that 50% of MS patients have abnormal regulation of serum cortisol levels as defined by the dexamethasone suppression test (DST). These nonsuppressors may compose the subgroup of patients who fail to respond to ACTH therapy. In earlier work with depressed patients, we demonstrated that cortisol nonsuppression is coincident with lymphocyte insensitivity to steroids in vitro and failure of lymphocyte glucocorticoid (GCC) receptor down regulation in vivo. This is relevant to MS in that MS patients have an increased incidence of depression and also have abnormalities in cortisol autoregulation. I propose to further investigate the relationship between abnormal cortisol responses in vivo (DST) and therapeutic and immunologic variables including the following: clinical response to ACTH therapy; lymphocyte surface antigens, immune function, and responses to steroids in vitro; and GCC receptor resonses to steroids in vivo and in vitro. In addition, we will study the ability of MS lymphocytes to secrete ACTH in tissue culture and in response to in vivo stimuli (i.e. exacerbation of MS). This lymphocyte production of ACTH will be related to the level of serum cortisol in MS patients and to direct effects of ACTH on lymphocytes to determine its biological significance. Through these assays, we hope to predict clinical responses to steroid therapy and to define basic neuroendocrine and immunological factors involved in the pathogenesis of MS. These studies should enhance understanding of a spectrum of neuroendocrine effects on immune function and immune-mediated disease.